Enantiomerically pure (R) or (S) compounds can be produced by causing compounds to undergo enantioselective reactions. Use of enantioselective catalysts which are capable of catalyzing asymmetric hydrogenations, enantioselective hydrogen displacements and allylic substitution reactions, among others, can facilitate the attainment of high optical yields. The present invention relates to novel chiral amidophosphine-phosphinite compounds and complexes of these compounds as ligands with Group VIII metals, which complexes may be used as enantioselective catalysts.
The present invention is concerned with novel chiral, amido-phosphine-phosphinite compounds, which are present in (R) or (S) form, of formula (I) 
wherein
R1 signifies C2-8-alkyl, C3-8-cycloalkyl or aryl-C1-4-alkyl,
R2 signifies C1-8-alkyl, C3-8-cycloalkyl, aryl-C1-4-alkyl or aryl and
R3 and R4 each independently signify C1-8-alkyl, C3-8-cycloalkyl, aryl-C1-4-alkyl, aryl or heteroaryl or R3 and R4 together with the respective phosphorus atom signify a 9-dibenzophospholyl, 9-phosphabicyclo[3.3.1]nonyl or 9-phosphabicyclo[4.2.1]nonyl group and
* denotes a chiral center.
The invention is also concerned with the manufacture of the amidophosphine-phosphinite compounds of formula I, complexes of these compounds as ligands with Group VIII metals and optionally with additional ligands as well as the use of the complexes as catalysts for enantioselective reactions such as e.g. asymmetric hydrogenations, enantioselective hydrogen displacements, allylic substitution reactions and the like.
The object of the present invention is to provide novel, chiral amidophosphine-phosphinite compounds which can be used in the form of the aforementioned complexes in enantioselective reactions and thereby facilitate high optical yields. The object is achieved by the chiral amidophosphine-phosphinite compounds of formula I.
The following definitions of the general terms are used in the present specification and apply irrespective of whether the terms appear as such or in combination.
The term xe2x80x9cC1-4-alkylxe2x80x9d, xe2x80x9cC1-8-alkylxe2x80x9d or xe2x80x9cC2-8-alkylxe2x80x9d signifies in the scope of the present invention a straight-chain or branched alkyl group with up to 4 or 8 carbon atoms such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert. butyl, pentyl, isopentyl, neopentyl, hexyl, tert. hexyl, heptyl, isoheptyl, octyl or isooctyl.
The term xe2x80x9cC3-8-cycloalkylxe2x80x9d embraces cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
The term xe2x80x9carylxe2x80x9d, alone or as part of xe2x80x9caryl-C1-4-alkylxe2x80x9d, signifies a phenyl or naphthyl group which in each case can be either unsubstituted or mono- or multiply-substituted. Substituents which come into consideration here are halogen, C1-8-alkyl and C1-8-alkoxy groups, halogenated C1-8-alkyl and C1-8-alkoxy groups, di(C1-8-alkyl)amino, tri(C1-4-alkyl)silyl (preferably trimethylsilyl) and phenyl, whereby several substituents present can be the same or different. In the case of xe2x80x9caryl-C1-4-alkylxe2x80x9d this preferably signifies unsubstituted benzyl.
The term xe2x80x9chalogenxe2x80x9d signifies fluorine, chlorine, bromine or iodine.
The term xe2x80x9cheteroarylxe2x80x9d signifies a 5- or 6-membered heterocyclic group having aromatic character, which has in the ring one or more hetero atoms from the group of nitrogen, oxygen and sulfur. Examples of 5-membered heterocyclic groups are pyrrolyl, thienyl and furyl, with pyridyl being an example of a 6-membered heterocyclic group. Moreover, the heterocyclic groups can be substituted in the same manner as the aryls set forth above and/or can have a fused benzene ring. Preferably, heteroaryl has no substituents.
The term xe2x80x9cC1-8-alkoxyxe2x80x9d signifies a straight-chain or branched alkoxy group with up to 8 carbon atoms, preferably with up to 4 carbon atoms.
Methoxy, ethoxy, propoxy, isopropoxy and butoxy are examples.
The term xe2x80x9chalogenated C1-8-alkylxe2x80x9d or xe2x80x9chalogenated C1-8-alkoxyxe2x80x9d signifies an alkyl or alkoxy group which in each case is substituted with one or more halogen atoms, especially chlorine or fluorine. Examples are trifluoromethyl, trichloromethyl and pentafluoromethyl and, respectively, fluoromethoxy and chloromethoxy.
Amidophosphine-phosphinite compounds of formula I are preferred in which independently of one another R1 signifies tert. butyl, R2 signifies methyl and R3 and R4 each signify cyclohexyl, phenyl, 3-5-xylyl, 3,5-di(trifluoromethyl)phenyl, 3,5-di(tert. butyl)phenyl, 3,5-di(tert. butyl)-4-methoxyphenyl or 2-furyl or R3 and R4 together with the phosphorus atom signify 9-dibenzophospholyl.
Preferably, R3 and R4 have the same significance.
Amidophosphine-phosphinite compounds of formula I in which R3 and R4 signify 3,5-di(tert. butyl)phenyl are especially preferred.
Particularly preferred amidophosphine-phosphinite compounds of formula I are:
(S)- or (R)-N-(Diphenylphosphanyl)-2-[(diphenylphosphanyl)oxy]-3,3,N-trimethyl-butyramide,
(S)- or (R)-N-(dicyclohexylphosphanyl)-2-[(dicyclohexylphosphanyl)-oxy]3,3,N-trimethyl-butyramide,
(S)- or (R)-N-[di-(2-furyl)-phosphanyl]-2-[(di-(2-furyl)-phosphanyl)oxy]-3,3,N-trimethyl-butyramide,
(S)- or (R)-N-(5H-dibenzophospholyl)-2-[(5H-dibenzophospholyl)oxy]-3,3,N-trimethyl-butyramide,
(S)- or (R)-N-[bis(3,5-dimethylphenyl)-phosphanyl]-2-[(bis(3,5-dimethylphenyl)-phosphanyl)oxy]-3,3,N-trimethyl-butyramide,
(S)- or (R)-N-[bis(3,5-di(trifluoromethyl)phenyl)-phosphanyl]-2-[(bis(3,5di(trifluoromethyl)phenyl)-phosphanyl)oxy]-3,3,N-trimethyl-butyramide,
(S)- or (R)-N-[bis(3,5-di(tert. butyl)phenyl)-phosphanyl]-2-[(bis(3,5-di-(tert. butyl)phenyl)-phosphanyl)oxy]-3,3,N-trimethyl-butyramide and
(S)- or (R)-N-[bis(3,5-di(tert. butyl)-4-methoxyphenyl)-phosphanyl]-2-[(bis(3,5-di(tert. butyl)-4-methoxyphenyl)-phosphanyl)oxy]-3,3,N-trimethyl-butyramide.
The amidophosphine-phosphinite compounds of formula I in accordance with the invention (in the role of ligands) form complexes with transition metals of Group VIII, especially with rhodium, iridium, ruthenium and palladium, and such complexes are likewise an object of the present invention; they can be used as catalysts for enantioselective reactions, especially for Aasymmetric hydrogenations, enantioselective hydrogen displacements and allylic substitution reactions.
These complexes in accordance with the invention of the compounds of formula I with transition metals of Group VIII can contain further ligands. Examples of such complexes, which are likewise in accordance with the invention, are especially optically active cationic and neutral rhodium, iridium, ruthenium and palladium complexes of formulas
The term xe2x80x9cneutral ligandxe2x80x9d (L) signifies an exchangeable ligand, especially an olefin, e.g. ethylene, propylene, cyclooctene, 1,5-hexadiene, norbornadiene or 1,5-cyclooctadiene; an aromatic, e.g. benzene, hexamethylbenzene or p-cymene; a nitrile, e.g. acetonitrile or benzonitrile; or a molecule of the solvent in which the complex is produced. This ligand can be exchanged in the hydrogenation. Where more than one such ligand is present (n=2), the ligands can be the same or different.
The term xe2x80x9coxygen acid or complex acidxe2x80x9d (source of the anion Axe2x88x92) signifies an acid from the group of H2SO4, HClO4, HBrO4, HIO4, HNO3, H3PO4, H3PO3 and CF3SO3H or a halogen complex with the element boron, phosphorus, arsenic, antimony or bismuth. Preferred representatives of both types of acids are HClO4, CF3SO3H, HPF6, HBF4, HB(phenyl)4, HB[3,5(CF3)2xe2x80x94C6H3]4, HSbF6 and HAsF6. The anion Axe2x88x92 is formed in each case by removing a hydrogen ion; examples are ClO, PF and BF.
The term xe2x80x9canionic coordinating ligandxe2x80x9d (B) embraces especially halogen, a carboxylic acid residue, a sulphonate residue, e.g. tosylate or methanesulphonate, a 1,3-diketonate, e.g. acetylacetonate, an optionally substituted phenolate, hydroxy, nitrate, nitrite, cyanate, rhodanide, cyanide, allyl and 2-methylallyl. When phenolate is substituted, C1-4-alkyl groups and halogen atoms especially come into consideration as substituents, with the substitution being single or multiple.
As the alkali metal ion (M+) or alkaline earth metal ion (M2+) there is especially suitable the sodium or potassium ion or, respectively, the calcium or magnesium ion.
The term xe2x80x9ctetrasubstituted ammonium ionxe2x80x9d (M+) signifies an anion consisting of a nitrogen atom and four identical or different substituents which are selected from the group of C1-8-alkyl, phenyl and benzyl, such as, for example, the anions (C1-8-alkyl)4N+, (phenyl)N+(C1-8-alkyl)3 and (benzyl)N+(C1-8-alkyl)3.
The term xe2x80x9chalogenxe2x80x9d (B, C2 or C3) embraces fluorine, chlorine, bromine and iodine. In the case of a complex of formula II-e in which B signifies halogen, the halogen can be derived from the corresponding alkali metal, alkaline earth metal or tetrasubstituted ammonium halide.
Preferred complexes in accordance with the invention of the compounds of formula I are the optically active cationic and neutral rhodium, iridium and ruthenium complexes of formulae II-a to II-k.
The process in accordance with the invention for the manufacture of the novel chiral compounds of formula I comprises reacting a compound of formula (III) 
wherein
R1 signifies C2-8-alkyl, C3-8-cycloalkyl or aryl-C1-4- alkyl,
R2 signifies C1-8-alkyl, C3-8-cycloalkyl, aryl-C1-4- alkyl or aryl, and
* denotes a chiral center
with a disubstituted chlorophosphane of the general formula (IV)
R3R4PClxe2x80x83xe2x80x83IV
wherein
R3 and R4 each independently signify C1-8-alkyl, C3-8-cycloalkyl, aryl-C1-4-alkyl, aryl or heteroaryl or R3 and R4 together with the phosphorus atom signify a 9-dibenzophospholyl, 9-phosphabicyclo[3.3.1]nonyl or 9-phosphabicyclo[4.2.1]nonyl group
in a solvent and in the presence of a base.
Suitably, the compound of formula III is dissolved in a solvent, preferably under an inert atmosphere, e.g. nitrogen or argon, and a base (the first) is added, which can usually be effected at room temperature. Then, the solution is cooled down considerably, suitably to about xe2x88x9280xc2x0 C., and subsequently the second base is added thereto followed slowly by the chlorophosphane, suitably dissolved in a solvent. The reaction starts even at the low temperature. Subsequently, the temperature can be increased gradually, conveniently to room temperature, and thereafter the thus-obtained product (the compound of formula I) can be isolated and purified according to methods known per se.
In the process in accordance with the invention bases which serve in the role of the xe2x80x9cfirst basexe2x80x9d are secondary or tertiary amines, especially dialkylamines or trialkylamines, e.g. dimethylamine, diethylamine, dipropylamine, diisopropylamine, trimethylamine, triethylamine and tripropylamine, and bases which serve in the role of the xe2x80x9csecond basexe2x80x9d are alkali metal alkyls or alkali metal aryls, e.g. propyllithium, butyllithium, phenyllithium, butylsodium and butylpotassium, i.e. a combination of a secondary or tertiary amine (first base) with an alkali metal alkyl or alkali metal aryl (second base). Diisopropylamine and butyllithium are especially preferred bases.
Suitable solvents are aliphatic hydrocarbons, preferably halogenated aliphatic hydrocarbons such as, for example, methylene chloride and chloroform; and aliphatic and cyclic ethers such as, for example, diethyl ether, tert. butyl methyl ether and 1,2-dimethoxyethane and, respectively, dioxan, furan and tetrahydrofuran; or mixtures of such solvents. Diethyl ether or tetrahydrofuran is preferably used as the solvent for the manufacture of the amidophosphine-phosphinite compounds.
For the isolation and purification of the product, the mixture is conveniently evaporated, the residue is taken up in a suitable solvent, especially in a lower aliphatic ether, e.g. diethyl ether, and, after removal of residual solid constituents by filtration, the filtrate is evaporated to dryness. The thusobtained chiral compound of formula I can be purified further by crystallization, especially from a lower aliphatic hydrocarbon, e.g. pentane.
The enantiomerically-pure (R)- or (S)-compounds of formula III in turn can be produced by the asymmetric hydrogenation of the corresponding xcex1-ketoamide R1COCONHR2 using enantiomerically-pure hydrogenation catalysts in a manner known per se [H.Takaya et. al., xe2x80x9cAsymmetric Hydrogenationxe2x80x9d, pages 1-39 in Catalytic Asymmetric Synthesis, Ed. Iwao Ojima, VCH Publishers, Inc., New York/Weinheim/Cambridge (1993) as well as the references cited at the end of the article].
It has surprisingly been found that the complexes of formulae II-a to II-n not only as such, i.e. in the form of the respective individual complex consisting of the ligands Y in accordance with the invention (the chiral amidophosphine-phosphinite compound of formula I), the group VIII metal and optionally further ligands, but also in the form of the individual components, act as catalysts for enantioselective reactions, e.g. asymmetric hydrogenations. The complexes of formulae II-a to II-n themselves can be produced from these components in a manner known per se: see, for example, J.A.C.S. 93, 3089-3091 (1971); J. Chem. Soc., Chem. Comm. 1990, 869-871; Tetr.: Asymm. 1(11), 3059-3062 (1996); ibid. 6(1), 11-14 (1995); F. R. Hartley, The Chemistry of Platinum and Palladium, Applied Science Publishers Ltd., London 1973; J. Chem. Soc., Chem. Comm. 1986, 1338-1339; Inorg. Chem. 30, 125-130 (1991); Organometallics 12, 1406-1415 (1993); as well as ibid 15, 2440-2449 (1996).
The complexes in accordance with the invention of the compounds of formula I with Group VIII metals, especially those of the aforementioned formulae II-a to II-k, are suitable, for example, for the catalysis of the asymmetric hydrogenation of compounds of formula V to compounds of formula VI 
wherein HX signifies a mineral acid from the group of HBF4, H2SO4, HPF6, HCl, HBr, HI, H3PO4, HSbF6, HClO4 and NaH2PO4 or a strong organic acid from the group of C1-8-alkylSO3H, picric acid, formic acid, lower alkyl- and arylcarboxylic acids, e.g. acetic acid, propionic acid and benzoic acid, and dicarboxylic acids e.g. oxalic acid, succinic acid, maleic acid and phthalic acid, and * denotes a chiral center.
The molar ratio (substrate:catalyst, commonly denoted as xe2x80x9cSICxe2x80x9d) between the compound of formula V to be hydrogenated and the metal complex which is used as the catalyst in accordance with any one of formulae II-a to II-k, conveniently lies between about 20 and about 80 000, preferably between about 500 and about 30,000. The hydrogenation is conveniently carried out at temperatures in the range of about 0xc2x0 C. to about 150xc2x0 C., preferably 10xc2x0 C. to 100xc2x0 C., and under a pressure of about 1 to about 200 bar (about 0.1 MPa to about 20 MPa), preferably 10 to 80 bar (1 MPa to 8 MPa).
The free base of the compounds of formula VI is a known and valuable intermediate for pharmaceutically usable end products, e.g. the antitussive dextromethorphan and the analgesic levorphanol.
The complexes in accordance with the invention are also suitable, for example, as catalysts for the asymmetric hydrogenation of compounds of formula VII to compounds of formula VIII 
wherein R5 signifies C1-8-alkyl, C1-8-alkyl, C1-8-alkoxy, phenyl, benzyl or a group N(R6)2 and R6 signifies hydrogen, C1-8-alkyl, phenyl or benzyl and * denotes a chiral center.
Cationic rhodium complexes of formula II-a are preferably used as the catalysts for this asymmetric hydrogenation.
The ratio between rhodium and the ligands in accordance with the invention (chiral amidophosphine-phosphinite compound of formula I) lies in the range of about 0.05 to about 5 mol, preferably of 0.5 to 2 mol, of rhodium per mol of ligand. The molar ratio between the compound of formula VII to be hydrogenated and rhodium in the complex of formula II-a, i.e. the substrate:catalyst ratio (S/C), conveniently amounts to about 20 to about 100,000, especially about 500 to about 50,000. The enantioselective hydrogenation of compounds of formula VII using a complex of formula II-a can be effected at temperatures of about 10xc2x0 C. to about 120xc2x0 C., preferably at about 10xc2x0 C. to about 60xc2x0 C. The hydrogenation is conveniently effected under a pressure of about 1 to about 150 bar (about 0.1 to about 15 MPa), preferably of 5 to 60 bar (0.5 to 6 MPa).
The compounds of formula VIII are valuable intermediates for the synthesis of retinoids, which can be used e.g. for the therapy and prophylaxis of dermatological disorders, e.g. acne and psoriasis [see, for example, Pure and Appl. Chem. 57, 741 (1985) as well as European Patent Publication 0 802 181 A1]. Further, the compounds of formula VIII, which can be converted by hydrolysis into phorenol and in a further reaction step into optically active actinol, are important intermediates for the production of 3-hydroxy-carotenoids, especially for the production of zeaxanthin [see Pure and Appl. Chem. 51, 535-564 (1979) and Helv. Chim. Acta 63, 1451-1455 (1980)].